Tissue adhesives have been suggested as alternatives in surgical procedures to physical means of connecting tissues such as sutures and staples. Tissue adhesives will hold cut or separated areas of tissue together to allow healing and/or serve as a barrier to leakage, depending on the application. The adhesive should break down or be resorbed and it should not hinder the progress of the natural healing process. Ideally, the agent should promote the natural mechanism of wound healing and then degrade.
Tissue adhesives are generally utilized in three categories:
i) Hemostasis (for example, by improving in vivo coagulation systems, tissue adhesion itself has a hemostatic aim and it is related to patient clotting mechanisms)
ii) Tissue sealing: primary aim is to prevent leaks of various substances, such as air or lymphatic fluids.
iii) Local delivery of exogenous substances such as medications, growth factors, and cell lines.
A number of classes of tissue adhesives have been investigated and used:                Fibrin sealants (otherwise referred to as fibrin glues)        Albumin-based compounds (glutaraldehyde glues)        Cyanoacrylates        Hydrogels (polyethylene glycol polymers)        Collagen-based adhesives        
Fibrin glue was first used for hemostasis in 1909. Fibrin glues were initially homemade in the operating room by surgeons, but became commercially available in Europe in the early 1980s and are now in widespread use. Overall, fibrin sealants are very well tolerated by patients (Spotnitz, 1995; Lee et al, 1991; Milne et al, 1995)
One accepted value of fibrin glues lies in their unique physiologic action, which mimics the early stages of the blood coagulation process and wound healing; the part of the normal coagulation cascade to produce an insoluble fibrin matrix. Fibrinogen is a plasma protein with a molecular weight of 340,000. The fibrinogen molecule consists of two identical subunits that each contains one alpha, beta, and gamma polypeptide chain linked by disulfide bonds. In the natural mechanism, fibrinogen polypeptides are cleaved to soluble fibrin monomers by the action of activated thrombin. These monomers are cross-linked into an insoluble fibrin matrix with the aid of activated factor XIII (FIG. 1). The adhesive qualities of consolidated fibrin sealant to the tissue may be explained in terms of covalent bonds between fibrin and collagen, or fibrin, fibronectin and collagen. Fibrin glues act as both a hemostatic agent and as a sealant. They are bioabsorbable (due to in vivo thrombolysis). Degeneration and reabsorption of the resulting fibrin clot is achieved during normal wound healing.
All fibrin sealants in use as of 2003 have two major ingredients, purified fibrinogen (a protein) and purified thrombin derived from human or bovine blood. Many sealants have two additional ingredients, human blood factor XIII and a substance called aprotinin, which is derived from cows' lungs. Factor XIII is a compound that strengthens blood clots by forming covalent cross-links between strands of fibrin. Aprotinin is a protein that inhibits the enzymes that break down blood clots.
The preparation and application of fibrin sealants are somewhat complicated. The thrombin and fibrinogen are freeze-dried and packaged in vials that must be warmed before use. The two ingredients are then dissolved in separate amounts of water. Next, the thrombin and fibrinogen solutions are loaded into a double-barreled syringe that allows them to mix and combine as they are deposited on the incision. Pieces of surgical gauze or fleece may be moistened with the sealant solutions to cover large incisions or stop heavy bleeding. Recent developments include a delivery system that forms a fibrin sealant from the patient's own blood within a 30-minute cycle, and uses a spraypen rather than a double-barreled syringe for applying the sealant. Nevertheless there remains the difficulty that the seal takes a significant period of time to form and reach strength sufficient to hold when under pressure. Typically 70% of its ultimate strength is reached in 10 minutes, and full strength in approximately 2 hours, which means that fibrin sealants are unsuitable for many applications (for example, sealing an incision in a blood vessel, since prolonged clamping would be required) and inconvenient in many other applications compared to traditional methods.
The use of tissue adhesives is one alternative method to traditional mechanical means for closing incisions. A second technique known as laser tissue welding relies on carbon dioxide or Nd: YAG lasers to produce thermal effects to “weld” tissue surfaces together. A variant of this technique is referred to as chromophore-assisted laser welding and uses a protein solder that contains a light-absorbent dye together with a laser that emits the appropriate wavelength light. Thus for example the dye fluorescein is used in combination with a 532 nm frequency-double Nd: YAG laser or indocyanine green is used with an 805 nm diode laser. In this technique the energy absorbed by the dye was generally thought to be released as heat so as to denature proteins and produce non-covalent bonds between the added protein solder and collagen in the surrounding tissue. However, Khadem et al. (1999) suggested that, depending on the dye used, there may be contributions from photochemical reactions that produce covalent cross-links between protein molecules. To test this hypothesis Khadem et al. prepared covalent conjugates between the dye chlorine6 and a globular, non-structural protein, bovine serum albumin (BSA). They found that a fibrinogen conjugate with chlorine6 was substantially aggregated and unsuitable for use as a solder. Therefore, to explore the effect of fibrinogen on weld strength, they mixed fibrinogen with bovine serum albumin-chlorine6 conjugate in one experiment and with free chlorine6 in another. Khadem et al. concluded that these solders performed particularly poorly compared to a BSA-chlorine6 conjugate. Thus the inclusion of the matrix protein fibrinogen in the mixture adversely affected the results achieved with a BSA-chlorine6 conjugate.
In U.S. Pat. No. 6,607,522 (Hamblin & Khadem) there is disclosed a method of welding tissue together comprising applying to at least one tissue a composition including a photosensitizer and a proteinaceous compound or lipid and irradiating the composition to promote adhesion of the tissue to a second tissue. Note the term “photosensitizer” as used therein refers to a compound capable of undergoing photoactivation by converting electromagnetic radiation into chemical energy in the form of reactive oxygen species like singlet oxygen, superoxide anion, hydroxyl radicals and the like. As in the Khadem paper, a fibrinogen conjugate with chlorine6 was prepared but was found to be substantially aggregated and unsuitable for use as a solder. Therefore, fibrinogen was mixed with a BSA-chlorine6 conjugate and with free chlorine6 to produce similarly poor results to those reported in the Khadem paper.
A photoactivable tissue sealant known as FOCALSEAL has been developed and is FDA approved. FOCALSEAL is a polyethylene glycol based synthetic hydrogel which has two components, a primer and a sealant, and is applied in two steps and then polymerised by the application of a blue-green light. The sealant does not bond covalently to tissue but rather creates a mechanical bond that requires interpolation of sealant into an irregular tissue surface. The sealant is a macromer consisting of a water-soluble polyethylene glycol molecule, a biodegradable polylactic acid, trimethylene carbonate, and a polymerizible acrylic ester. An eosin-based primer penetrates the tissue, cross-links with itself, and provides a mechanical interlink to the sealant compound. The primer and sealant work in unison; the primer provides tissue penetration and tissue clearance and the sealant contributes desirable elastic properties. The primer also helps initiates the photo-polymerization of the sealant's acrylic ester group upon exposure to the light source.